E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma
E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma
复制标题
E2F1通过miR-26b调节食管鳞状细胞癌中细胞DNA损伤反应，促进癌细胞对顺铂的敏感性
DOI：
10.7150/jca.33983
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Dai, Limeng
中科院分区：
文献类型：
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作者：
Zhang, Kun;Zhang, Bo;Dai, Limeng
顺铂是治疗食管鳞癌的重要化疗药物。有研究表明，顺铂作用后，E2F1在ESCC细胞中的表达增加，但其机制尚不清楚。在这里，我们发现在顺铂处理的ESCC细胞中miR-26b表达上调，并且它依赖于E2F1的表达，因为E2F1直接与miR-26b基因的启动子结合，从而激活miR-26b的转录活性。细胞周期分析表明，miR-26b抑制了癌细胞的G1/S期转变，从而抑制了癌细胞的生长。顺铂诱导的细胞周期停滞也与miR-26b的表达密切相关。体内实验表明，当E2F1/miR-26b通路被干扰时，ESCC细胞对顺铂的敏感性降低。顺铂治疗的裸鼠移植瘤模型显示，与单纯顺铂治疗组相比，Si-E2F1组的肿瘤体积增大。这种作用可能与细胞DNA损伤反应有关，因为miR-26b可以通过与ATM和Rb基因的3‘端非编码区结合，靶向ATM和Rb基因的mRNA，从而导致ATM和Rb蛋白表达下降。综上所述，我们的结果表明，E2F1促进了食管癌顺铂的化疗增敏作用。这种作用可能与miR-26b上调有关，因为顺铂诱导的细胞周期停滞依赖于miR-26b，miR-26b也可能通过减少ATM和Rb的表达来干扰DNA损伤反应。
Cisplatin is an essential chemotherapy drug in esophageal squamous cell carcinoma (ESCC). Some studies suggested that the expression of E2F1 is increased in ESCC cells after cisplatin treatment, but its mechanism remains obscure. Here, we found that miR-26b is upregulated in ESCC cell lines with cisplatin treatment, and it relies on the expression of E2F1 because E2F1 directly binds to the promoter of the miR-26b gene, thus activating the transcriptional activity of miR-26b. Cell cycle analysis suggested that miR-26b inhibits the G1/S phase transition, thus inhibiting the cell growth of ESCC cells. The cisplatin-induced cycle arrest also closely depends on the expression of miR-26b. In vivo assays revealed that the sensitivity of ESCC cells to cisplatin is decreased when the E2F1/miR-26b pathway is disturbed. A nude mouse xenograft model of cisplatin treatment showed that the tumor volume was increased in the Si-E2F1 group compared with that in the group with cisplatin treatment alone. The effect may be due to the cellular DNA damage response, because that miR-26b could target the mRNA of ATM and Rb genes via binding to their 3'UTRs, thus leading to decreased protein expression of ATM and Rb. In conclusion, our results indicate that E2F1 promotes the chemosensitization to cisplatin in ESCC. The effect may be due to the upregulation of miR-26b because cisplatin-induced cycle arrest depends on miR-26b, which may also disturb the DNA damage response by reducing the expression of ATM and Rb.